Diffusion tensor imaging (DTI) has been used to study microstructural white matter alterations in a variety of conditions including normal aging and Alzheimer's disease (AD). White matter hyperintensities (WMH) are common in cognitively healthy elderly as well as in AD and exhibit elevated mean diffusivity (MD) and reduced fractional anisotropy (FA). However, the effect of WMH on statistical analysis of DTI estimates has not been thoroughly studied. In the present study we address this in two ways. First, we investigate the effect of WMH on MD and FA in the dorsal and ventral cingulum, the superior longitudinal fasciculus, and the corticospinal tract, by comparing two matched groups of cognitively healthy elderly (n = 21 + 21) with unequal WMH load...

Pathophysiological changes of Alzheimer's Disease (AD) begin decades before clinical symptoms become apparent, providing an important window for early diagnosis and intervention. Prodromal stage of AD, a great opportunity for effective treatment and postponing the disease onset, has drawn extensive attention. The application of different biomarkers including neuroimaging, biochemical substances and genes makes AD-related pathology detectable in vivo and exploring novel biomarkers with relatively non-invasive and low cost has intrigued a wide range of interests...

BACKGROUND: Composite scales have recently been proposed as outcome measures for clinical trials. For example, the Prodromal Alzheimer's Cognitive Composite (PACC) is the sum of z-score normed component measures assessing episodic memory, timed executive function, and global cognition. Alternative methods of calculating composite total scores using the weighted sum of the component measures that maximize signal-to-noise of the resulting composite score have been proposed. Optimal weights can be estimated from pilot data, but it is an open question how large a pilot trial is required to calculate reliably optimal weights...

Acetylcholinesterase inhibitors are approved drugs currently used for the treatment of Alzheimer's disease (AD) dementia. Basal forebrain cholinergic system (BFCS) atrophy is reported to precede both entorhinal cortex atrophy and memory impairment in AD, challenging the traditional model of the temporal sequence of topographical pathology associated with AD. We studied the effect of one-year Donepezil treatment on the rate of BFCS atrophy in prodromal AD patients using a double-blind, randomized, placebo-controlled trial of Donepezil (10 mg/day)...

BACKGROUND: The use of imaging markers for the diagnosis of predementia and early dementia stages of Alzheimer's disease (AD) has widely been explored in research settings and specialized care. The use of these markers in primary care has yet to be established. OBJECTIVE: Summarize current evidence for the usefulness of imaging markers for AD in primary compared to specialized care settings. METHOD: Selective overview of the literature, and pilot data on the use of MRI-based hippocampus and basal forebrain volumetry for the discrimination of AD dementia and mild cognitive impairment (MCI) cases from healthy controls in 58 cases from a primary care cohort and 58 matched cases from a memory clinic's sample...

INTRODUCTION: Assessing cognitive and functional changes at the early stage of Alzheimer's disease (AD) and detecting treatment effects in clinical trials for early AD are challenging. METHODS: Under the assumption that transformed versions of the Mini-Mental State Examination, the Clinical Dementia Rating Scale-Sum of Boxes, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale tests'/components' scores are from a multivariate linear mixed-effects model, we calculated the sample sizes required to detect treatment effects on the annual rates of change in these three components in clinical trials for participants with mild cognitive impairment...

The alteration of the default mode network (DMN) functional connectivity (FC) has been reported in patients with amnestic mild cognitive impairment (aMCI) as a predictor of Alzheimer's disease (AD). However, no studies exist that examined stage-dependent DMN FC changes throughout the course of aMCI. The present study aims to characterize patterns of DMN FC over three aMCI stages as first defined. Utilizing the extreme groups approach on the performance of memory tasks, aMCI subjects were divided into mild, moderate, and severe stages...

Alzheimer's disease (AD) is a neurodegenerative disorder accompanied by severe progressive memory and cognitive impairment. The brain of AD patients has an abundance of two abnormal structures, amyloid plaques (senile plaques) and neurofibrillary tangles. In addition, drebrin loss is another hallmark of AD brains, which is a common feature in the brain of both AD patients and AD mouse models. Strong evidence from human genetics and transgenic mouse models has indicated that amyloid β (Aβ) is part of the etiology and pathogenesis of AD...

BACKGROUND: Existing indices of white matter integrity such as fractional anisotropy and magnetization transfer ratio may not provide optimal specificity to myelin content. In contrast, myelin water fraction (MWF) derived from the multiecho T2 relaxation time technique may serve as a more direct measure of myelin content. PURPOSE/HYPOTHESIS: The goal of the present study was to identify markers of regional demyelination in patients with probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in relation to age and severity of neuropsychiatric impairment...

BACKGROUND AND OBJECTIVE: The differentiation of mild cognitive impairment (MCI), which is the prodromal stage of Alzheimer's disease (AD), from normal control (NC) is important as the recent research emphasis on early pre-clinical stage for possible disease abnormality identification, intervention and even possible prevention. METHODS: The current study puts forward a multi-modal supervised within-class-similarity discriminative dictionary learning algorithm (SCDDL) we introduced previously for distinguishing MCI from NC...

Numerous studies have reported an association between shortened leukocyte telomere length (LTL) and increased risk of Alzheimer's disease (AD). In this study we investigated the relationship between LTL and AD development, including in the analysis patients with amnestic mild cognitive impairment (aMCI), a clinical entity considered prodromal of AD. LTL (T/S ratio) was measured in patients with AD (n=61) or aMCI (n=46), and compared with LTL of age-matched controls (n=56). Significant LTL differences were observed between controls, aMCI and AD patients (p<0...

Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576-AβPPswe mice...

Tremendous progress has been made over the last few years in understanding how sleep and amyloid-β (Aβ) cooperate to speed up the progression of Alzheimer's disease (AD). However, it remains unknown whether sleep deficits also interact with other risk factors that exacerbate the pathological cascade of AD. Based on evidence showing that higher levels of homocysteine (HCY) and sleep loss increase oxidative damage, we here investigate whether the relationship between HCY and total antioxidant capacity (TAC) is mediated by changes in objective sleep in healthy older (HO, N = 21) and mild cognitive impairment (MCI, N = 21) subjects...

BACKGROUND: MRI-based hippocampus volume is a core clinical biomarker for identification of Alzheimer's disease (AD). OBJECTIVE: To assess robustness of automatic hippocampus volumetry with the freely available FSL-FIRST software with respect to short-term repeat and across field strength imaging. FSL-FIRST hippocampus volume (FIRST-HV) was also evaluated as enrichment biomarker for mild cognitive impairment (MCI) trials. METHODS: Robustness of FIRST-HV was assessed in 51 healthy controls (HC), 74 MCI subjects, and 28 patients with AD dementia from ADNI1, each with two pairs of back-to-back scans, one at 1...

Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD...

BACKGROUND: β-Amyloid (Aβ) is the product of concerted cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, the molecular mechanisms that regulate this process are not well understood. Recently, evidence was reported that γ-secretase activating protein (GSAP, 16 kDa), derived from a larger precursor protein (98 kDa), plays a role in Aβ metabolism through a mechanism involving its interaction with both γ-secretase and APP. However, a detailed evaluation of GSAP protein levels and their association with clinical and neuropathological variables are lacking during the clinical progression of Alzheimer disease (AD)...

A set of core cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) includes total tau (T-tau), phosphorylated tau (P-tau) and β-amyloid 42 (Aβ42). These biomarkers reflect some of the key aspects of AD pathophysiology, including neuronal degeneration, tau phosphorylation with tangle formation, and Aβ aggregation with deposition of the peptide into plaques. The core AD CSF biomarkers have been validated clinically in numerous studies, and found to have a very high diagnostic performance to identify AD, both in the dementia and in the mild cognitive impairment stages of the disease...